Abstract: Our funded R01 is based on the discovery that FGFBP1 is associated with synapses and progressively decreases with advancing age and in Amyotrophic Lateral Sclerosis (ALS). Specifically, we have discovered that genetic deletion of FGFBP1 accelerates degeneration of the neuromuscular synapse during normal aging and progression of ALS. Since FGF ligands are present and play critical functions in the brain, our findings suggest that FGFBPs, which are master regulators of FGF ligand signaling, may play similar roles in brain synapses harboring AD-inducing factors and with advancing age. Additionally, the increased presence of glycosylated ECM proteins in amyloid plaques and elsewhere due to fibrosis in AD strongly indicates that changes in levels and secretion of FGFBPs would further compromise FGF signals in AD. Thus, there is a strong rationale to posit that FGFBPs may be necessary for FGF ligands to appropriately promote the maintenance, repair, and survival of synapses and neurons most susceptible to AD. In this study, we propose to evaluate the role of FGFBPs in AD in the following two aims: 1) We will determine the expression and distribution of FGFBPs in brain regions affected with AD. 2) We will test the hypothesis that FGFBP1 plays important roles in AD pathogenesis in mouse models of AD and in cultured neurons harboring AD-causing mutant genes.